Although percutaneous coronary intervention (PCI) modalities such as angioplasty are often used as the standard procedure for treatment of cardiovascular disease, the number one cause of death in the U.S., they have many limitations including late restenosis and thrombosis. Delayed endothelium regeneration after vascular injury by PCI has been indicated as a major cause for these drawbacks, especially late thrombosis. Indeed, endothelium layer serves as a nature barrier for the artery and plays an important role in the prevention of platelet adhesion and smooth muscle cell proliferation and migration. Thus our long-term goal is to engineer novel multifunctional targeting nanoparticles (MTNs) that can bind specifically onto the injured arterial site to serve as a temporary barrier to prevent platelet adhesion and smooth muscle cell migration while recruiting stem cells such as endothelial progenitor cells (EPCs) for enhancing endothelium regeneration. The novel engineered MTNs will prevent platelet adhesion and encourage rapid endothelium healing at the injured site, allowing the potential of re-endothelialization in situ. To reach our goal, three specific aims are proposed: (1) To synthesize and characterize novel biodegradable, biocompatible, and hemo-compatible biomaterials including urethane-doped polyesters (UPEs) for vascular tissue engineering applications. (2) To formulate MTNs, which are made of UPEs, loaded with therapeutic reagents including growth factors, and conjugated with both the injured arterial wall targeting ligands and the EPC binding molecules. Various properties of MTNs including the effects of MTNs on platelet deposition and endothelium regeneration in vitro will be further investigated. (3) To determine the effectiveness of novel MTNs in vivo for endothelium regeneration in situ following PCI injury using animal models. There are several innovative aspects associated with this research. Our engineered MTNs, based on recent advances in both tissue engineering and nanotechnology, provide a unique strategy to promote endothelium regeneration and hence to stimulate vascular healing after PCI while preventing platelet adhesion. Another novel aspect of our research is that the engineered MTNs utilize the combination of (1) targeting injured arteries, (2) reducing platelet adhesion by serving as a temporary barrier, (3) capturing EPC at the targeted sites, which indirectly reduce platelet deposition on the damaged areas, and (4) promoting endothelium regeneration using engineered tissue nanoscaffolds. The proposed MTNs will bring in a significant improvement in the treatment of PCI-associated vascular injury and should generate highly scientific and economic impacts in cardiovascular disease therapy.